Anesthetic key points in a patient with a terminal ileum neuroendocrine tumor and a rare carcinoid left heart disease presented for non-cardiac surgery: case report.

BACKGROUND: Carcinoid tumors are rare neuroendocrine malignancies presenting in an increasing number in our center. The incidence of carcinoid tumors is approximatively between 2.5 and 5 cases per 100,000 people of whom about 50% develop carcinoid syndrome. Once the carcinoid syndrome has developed, a carcinoid cardiomyopathy can occur. Carcinoid heart disease (CaHD) remains a serious and rare complication associated with a significant increase in morbidity and mortality. Although carcinoid tumors have been known and studied for several years, there are still scarce data on the anesthetic management and the peri operative period. CASE PRESENTATION: We describe a case of a Caucasian 44-year-old woman with an unusual presentation of left CaHD with an ileal neuroendocrine tumor and liver metastases. Our preoperative somatostatin administration protocol, limit the cardiac damage. The maintenance of stable hemodynamics, the use of balanced anesthetic technique, all along with a good understanding of the pathology, played a major role in the successful management of anesthesia. This case report allows us to introduce our decision algorithm for the management of this type of pathology in our tertiary hospital, Cliniques Universitaires Saint-Luc. CONCLUSION: Despite the paucity of data, anesthetic management of patients with carcinoid tumor can be safely performed with effective hemodynamic monitoring and a good understanding of the pathophysiology. Knowledge and application of a clear institutional algorithm for octreotide administration and multidisciplinary consultation at a referral center are essential for the management of these patients.

The single-cell transcriptional landscape of lung carcinoid tumors.

Lung carcinoid tumors, also referred to as pulmonary neuroendocrine tumors or lung carcinoids, are rare neoplasms of the lung with a more favorable prognosis than other subtypes of lung cancer. Still, some patients suffer from relapsed disease and metastatic spread. Several recent single-cell studies have provided detailed insights into the cellular heterogeneity of more common lung cancers, such as adeno- and squamous cell carcinoma. However, the characteristics of lung carcinoids on the single-cell level are yet completely unknown. To study the cellular composition and single-cell gene expression profiles in lung carcinoids, we applied single-cell RNA sequencing to three lung carcinoid tumor samples and normal lung tissue. The single-cell transcriptomes of carcinoid tumor cells reflected intertumoral heterogeneity associated with clinicopathological features, such as tumor necrosis and proliferation index. The immune microenvironment was specifically enriched in noninflammatory monocyte-derived myeloid cells. Tumor-associated endothelial cells were characterized by distinct gene expression profiles. A spectrum of vascular smooth muscle cells and pericytes predominated the stromal microenvironment. We found a small proportion of myofibroblasts exhibiting features reminiscent of cancer-associated fibroblasts. Stromal and immune cells exhibited potential paracrine interactions which may shape the microenvironment via NOTCH, VEGF, TGFß and JAK/STAT signaling. Moreover, single-cell gene signatures of pericytes and myofibroblasts demonstrated prognostic value in bulk gene expression data. Here, we provide first comprehensive insights into the cellular composition and single-cell gene expression profiles in lung carcinoids, demonstrating the noninflammatory and vessel-rich nature of their tumor microenvironment, and outlining relevant intercellular interactions which could serve as future therapeutic targets.

Prognostic nomogram for predicting long-term cancer-specific survival in patients with lung carcinoid tumors.

BACKGROUND: Lung carcinoid is a rare malignant tumor with poor survival. The current study established a nomogram model for predicting cancer-specific survival (CSS) in patients with lung carcinoid tumors. METHODS: A total of 1956 patients diagnosed with primary lung carcinoid tumors were extracted from the Surveillance, Epidemiology, and End Results database. The specific predictors of CSS for lung carcinoid tumors were identified and integrated to build a nomogram. Validation of the nomogram was conducted using parameters concordance index (C-index), calibration plots, decision curve analyses (DCAs), and the receiver operating characteristic (ROC) curve. RESULTS: Age at diagnosis, grade, histological type, N stage, M stage, surgery of the primary site, radiation of the primary site, and tumor size were independent prognostic factors of CSS. High discriminative accuracy of the nomogram model was shown in the training cohort (C-index = 0.873), which was also testified in the internal validation cohort (C-index = 0.861). In both cohorts, the calibration plots showed good concordance between the predicted and observed CSS at 3, 5, and 10 years. The DCA showed great potential for clinical application. The ROC curve showed superior survival predictive ability of the nomogram model (area under the curve = 0.868). CONCLUSIONS: We developed a practical nomogram that provided independent predictions of CSS for patients with lung carcinoid tumors. This nomogram may have the potential to assist clinicians in prognostic evaluations or developing individualized therapies for patients with this neoplasm.

Effect of treatment center volume on outcomes in gastroenteropancreatic neuroendocrine tumor patients.

BACKGROUND: Medical centers with varying levels of expertise treat gastroenteropancreatic neuroendocrine tumors (GEP-NETs), which are relatively rare tumors. This study assesses the impact of center volume on GEP-NET treatment outcomes. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) registry linked to Medicare claims data. The data includes patients diagnosed between 1995 and 2010 who had no health maintenance organization (HMO) coverage, participated in Medicare parts A and B, were older than 65 at diagnosis, had tumor differentiation information, and had no secondary cancer. We identified medical centers at which patients received GEP-NET treatment (surgery, chemotherapy, somatostatin analogues, or radiation therapy) using Medicare claims data. Center volume was divided into 3 tiers - low, medium, and high - based on the number of unique GEP-NET patients treated by a medical center over 2 years. We used Kaplan-Meier curves and Cox regression to assess the association between volume and disease-specific survival. RESULTS: We identified 899 GEP-NET patients, of whom 37, 45, and 18% received treatment at low, medium volume, and high-volume centers, respectively. Median disease-specific survival for patients at low and medium tiers were 1.4 years and 5.3 years, respectively, but was not reached for patients at high volume centers. Results showed that patients treated at high volume centers had better survival than those treated in low volume centers (HR: 0.63, 95% CI: 0.4-0.9), but showed no difference in outcomes between medium and high-volume centers. CONCLUSIONS: Our results suggest that for these increasingly common tumors, referral to a tertiary care center may be indicated. Physicians caring for GEP-NET patients should consider early referral to high volume centers.

Sensitivity and Specificity of the NETest: A Validation Study.

BACKGROUND: Secretory tumor markers traditionally measured in patients with neuroendocrine tumors (NET) are lacking sensitivity and specificity, and consequently they are of limited clinical utility. The NETest, a novel blood multigene RNA transcript assay, has been found to be highly sensitive and specific. We sought to validate the sensitivity of the NETest in a population of metastatic well-differentiated NETs of gastroenteropancreatic and lung origin and to evaluate NETest specificity in a mixed population of metastatic non-NET gastrointestinal (GI) malignancies and healthy individuals. DESIGN AND METHODS: Forty-nine patients with metastatic NETs, 21 patients with other metastatic GI cancers, and 26 healthy individuals were enrolled in the study. Samples were sent in a blinded fashion to a central laboratory, and an NETest value of 0-13% was considered normal. RESULTS: Using 13% as the upper limit of normal, the sensitivity of the NETest was 98% (95% CI 89-100%). The overall specificity was 66% (95% CI 51-79%), with 16 false-positive results. Specificity was 81% (95% CI 62-92%) among 26 healthy individuals and 48% (95% CI 26-70%) among patients with other GI malignancies. Using an updated normal range of 0-20%, sensitivity was unchanged, but specificity improved to 100% among healthy participants and to 67% among patients with other cancers. CONCLUSIONS: The sensitivity of the NETest is exceptionally high (>95%) in a population of metastatic, well-differentiated NETs. Specificity within a healthy population of patients is exceptionally high when using a normal range of 0-20% but relatively low when evaluating patients with other GI malignancies.

Bone Metastases in Neuroendocrine Tumors: Molecular Pathogenesis and Implications in Clinical Practice.

Skeletal colonization is often regarded as a rare event in patients with neuroendocrine tumors (NETs) although both national registries and retrospective series report an incidence of bone metastases as high as 20% in subjects with advanced disease. While the biological mechanisms leading to bone metastatic colonization in NETs have been poorly investigated so far, key steps of osteotropic mechanisms, including the epithelial-to-mesenchymal transition, preparation of the premetastatic niche, migration of circulating tumor cells towards the bone marrow as well as the resulting alterations of the skeletal metabolism, are likely to operate also during the development of NET bone metastases. The skeleton involvement by NETs has a detrimental impact on both quality of life and patients' prognosis, leading to pain in the majority of symptomatic subjects. While it is currently unclear whether or not the earlier recognition of bone involvement by PET/CT imaging techniques employing 68Ga-DOTA-conjugated peptides might improve outcomes through the exploitation of timely treatments, the management of bone-colonizing NETs is today based only on clinical experience from other osteotropic tumors. Here, we summarize the fundamental molecular mechanisms driving bone colonization and revisit both established and novel treatments for patients with bone metastatic NETs.

Extra-appendicular neuroendocrine tumors: A report from the TREP project (2000-2020).

BACKGROUND: Extra-appendicular neuroendocrine tumors (NETs) are very rare tumors. While diagnostic and therapeutic guidelines are well established for adults, data on children and adolescents are lacking. PATIENTS AND METHODS: Patients with a diagnosis of extra-appendicular NET registered on the Tumori Rari in Età Pediatrica - Rare Tumors in Pediatric Age (TREP) from 2000 to 2020 were analyzed. Clinical characteristics including patients' presentation, tumor features, treatment, and outcome were reviewed. RESULTS: Twenty-seven patients with extra-appendicular NET registered on TREP with a median age of 173 months. The primary site was the pancreas (12) or bronchi (10) in the majority of cases. Other primary sites included the thymus, Meckel's diverticulum, and liver. Thirteen (48%) of tumors extended beyond the organ of origin: four invaded neighboring organs and/or regional nodes and nine involved distant metastases. The 3-year event-free survival (EFS) for those with localized disease was superior to those with metastatic disease (66.6% 95% CI 5-95% vs 33% 95% CI 5-68%, respectively; P = .005). A complete resection was feasible in 17 patients. The 3-year EFS in these patients was superior to those with no or incomplete resection (R0 vs R1/R2, respectively; P = .007). Overall, 16 children had no evidence of disease at follow-up, and one is alive with disease; five died, and five were lost to follow-up. CONCLUSIONS: Data from our experience demonstrated a wide heterogeneity of presentation and outcome of these tumors. Localized disease and complete surgical resection were the main prognostic factors of good outcome. Other therapies may have a role in prolonging survival in metastatic disease.

Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study.

BACKGROUND: Despite a protracted disease course and multiple available therapies, patients with well-differentiated neuroendocrine tumors (NETs) inevitably experience disease progression. Programmed death-ligand 1 (PD-L1) has been associated with NET progression and prognosis. The multicohort, phase 1 KEYNOTE-028 study (ClinicalTrials.gov identifier NCT02054806) evaluated the activity and safety of the anti-programmed cell death protein 1 immunotherapy pembrolizumab in patients with well-differentiated or moderately-differentiated NETs. METHODS: Patients with PD-L1-positive, locally advanced or metastatic carcinoid or well-differentiated or moderately-differentiated pancreatic NETs (pNETs) were enrolled into separate cohorts and received pembrolizumab at a dose of 10 mg/kg every 2 weeks for up to 2 years. The objective response rate was the primary endpoint (as per Response Evaluation Criteria in Solid Tumors version 1.1, by investigator review). Safety was a secondary endpoint. RESULTS: Of 170 and 106 patients, respectively, who had evaluable samples among those screened for the carcinoid and pNET cohorts, 21% and 25%, respectively, had PD-L1-positive tumors; of these, 25 and 16 patients, respectively, were eligible and treated. The median follow-up was 20 months (range, 2-35 months) and 21 months (range, 5-32 months), respectively. The objective response rate was 12.0% (95% CI, 2.5%-31.2%) and 6.3% (95% CI, 0.2%-30.2%), respectively; 3 partial responses occurred among the carcinoid cohort and 1 among the pNET cohort. The median duration of response in the carcinoid cohort was 9.2 months (range, 6.9-11.1 months), and was not reached in the pNET cohort. No complete responses occurred. Treatment-related adverse events occurred in 68% and 69% of patients, respectively, most often diarrhea (7 patients in the carcinoid cohort and 4 patients in the pNET cohort) and fatigue (6 patients in each cohort). Hypothyroidism was the most common immune-mediated adverse event (5 patients in the carcinoid cohort and 2 patients in the pNET cohort). CONCLUSIONS: Pembrolizumab demonstrated antitumor activity in a subset of patients with NETs and was well-tolerated.

Epidemiology of Large Bowel Carcinoid Tumors in the USA: A Population-Based National Study.

BACKGROUND AND AIMS: Prior studies have shown that about 90% of all carcinoid tumors occur in the GI tract. However, epidemiological studies of these tumors have been limited by small sample size. Our aim was to obtain a more robust epidemiologic survey of large bowel carcinoids (LBC), using population-based data in order to more accurately identify risk factors for these tumors. METHODS: We used a commercial database (Explorys Inc, Cleveland, OH) which includes electronic health record data from 26 major integrated US healthcare systems. We identified all patients aged 18 and older who were diagnosed with LBC, excluding appendiceal carcinoids, between 1999 and 2018 based on Systematized Nomenclature Of Medicine-Clinical Terms (SNOMED-CT) and evaluated the prevalence of LBC. We also performed univariate analysis to describe age-, race-, and gender-based distributions and to identify potential risk factors. RESULTS: Of the 62,817,650 individuals in the database, 4530 were identified to have LBC with an overall prevalence of 7.21/100,000. Individuals with LBC were more likely to be elderly (age > 65) [OR 2.17, CI 2.05-2.31, p < 0.0001], smokers [OR 3.25; 95% CI 3.00-3.53, p < 0.0001], have a history of alcohol use [OR 3.75; 95% CI 3.52-3.99, p < 0.0001], diabetes mellitus (DM) [OR 4.42; 95% CI 4.14-4.72, p < 0.0001], obesity [OR 1.58; 95% CI 1.43-1.74, p < 0.0001], family history of cancer [OR 8.06; 95% CI 7.47-8.71, p < 0.0001], and personal history of ulcerative colitis [OR 6.93; 95% CI 5.55-8.64, p < 0.0001] or Crohn's disease [OR 6.45; 95% CI 5.24-7.95, p < 0.0001]. The prevalence of LBC was less among Caucasians compared to African-Americans [OR 0.57; 95% CI 0.53-0.61, p < 0.0001]. There was no statistically significant gender-based difference; men versus women [OR 1.02; 95% CI 0.96-1.08, p = 0.47]. The most common presenting symptoms included flushing, diarrhea, nausea, weight loss, and abdominal pain, while the most common GI associations included perforation, obstruction, hemorrhage, intussusception, and volvulus. CONCLUSION: This is the largest epidemiological study evaluating the prevalence of LBC. We estimated the prevalence rate of LBC to be 7.21/100,000. The presence of significant risk factors with the clinical picture suspicious for a LBC should warrant thorough evaluation as these tumors can lead to life-threatening complications. Further studies are needed to better understand the mechanism of association between these risk factors and LBC.

The Tumor Microenvironment in Neuroendocrine Tumors: Biology and Therapeutic Implications.

Neuroendocrine tumors (NETs) include a heterogeneous group of malignancies arising in the diffuse neuroendocrine system and characterized by indolent growth. Complex interactions take place among the cellular components of the microenvironment of these tumors, and the recognition of the molecular mediators of their interplay and cross talk is crucial to discover novel therapeutic targets. NET cells overexpress a plethora of proangiogenic molecules including vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, semaphorins, and angiopoietins that promote both recruitment and proliferation of endothelial cell precursors, thus resulting among the most vascularized cancers with a microvessel density 10-fold higher than epithelial tumors. Also, NETs operate multifaceted interactions with stromal cells, both at local and distant sites, and whether their paracrine secretion of serotonin, connective tissue growth factor, and transforming growth factor ß primarily drives the fibroblast activation to enhance the tumor proliferation, on the other side NET-derived profibrotic factors accelerate the extracellular matrix remodeling and contribute to heart valves and/or mesenteric fibrosis development, namely, major complications of functioning NETs. However, at present, little is known on the immune landscape of NETs, but accumulating evidence shows that tumor-infiltrating neutrophils, mast cells, and/or macrophages concur to promote the neoangiogenic switch of these tumors by either direct or indirect mechanisms. On the other hand, immune checkpoint molecules are heterogeneously expressed in NETs' surrounding cells, and it is unclear whether or not tumor-infiltrating lymphocytes are antitumor armed within the microenvironment, given their low mutational load. Here, we review the current knowledge on both gastroenteropancreatic and pulmonary NETs' microenvironment as well as both established and innovative treatments aimed at targeting the tumor-host interplay.

Case report: optimal tumor cytoreduction and octreotide with durable disease control in a patient with MEN-1 and Zollinger-Ellison syndrome-over a decade of follow-up.

BACKGROUND: Zollinger-Ellison syndrome (ZES) is a rare condition characterized by hypersecretion of gastrin by gastrinoma tumors leading to severe peptic ulcer disease with potential development of gastric carcinoid tumors. Herein, we report the clinical course of a 68-year-old patient with multiple endocrine neoplasia type 1 (MEN-1) who underwent several surgeries to ultimately undergo optimal tumor cytoreduction of locally advanced gastrinomas and symptomatic gastric carcinoids. The patient was subsequently maintained on octreotide long-acting release (LAR). This case report supports consideration for aggressive tumor cytoreduction and octreotide in similar patients with MEN-1-associated ZES for durable disease control and symptom management. CASE PRESENTATION: The patient is a 68-year-old male with multiple endocrine neoplasia type 1 (MEN-1), diagnosed in 1993 after presenting with recurrent renal calculi and hypercalcemia. Soon thereafter, he presented with symptoms and elevated gastrin levels suggestive of ZES prompting abdominal exploration with partial resection of the duodenum to remove gastrinoma tumor nodules. Within 4 years of the operation, he represented with intractable hypergastrinemia despite optimal medical management with peak gastrin levels exceeding 29,000 pg/mL, in 2006. In January 2007, the patient returned to the operating room for resection of regional peripancreatic and perigastric lymph nodes and enucleation of pancreatic body and tail gastrinoma tumors. Although his gastrin level decreased to 5000 pg/mL with resultant improvement of symptoms, in less than 2 years, he developed disease progression with obstructive symptomatology from enlarging gastric carcinoids and rising gastrin levels. In May of 2008, he underwent pancreaticoduodenectomy and near-total gastrectomy. Since June of 2008, the patient shows no demonstrable progression of disease and remains asymptomatic on LAR octreotide (30 mgs). Gastrin levels have been well controlled (range, 100-624 pg/mL; current 114 pg/mL). CONCLUSION: Success of this procedure in our case report highlights the potential role for optimal tumor cytoreduction and LAR octreotide to control disease progression in a patient with MEN-I and Zollinger-Ellison syndrome with locally advanced gastrinoma and secondary large gastric carcinoids.

Pulmonary Carcinoids and Low-Grade Gastrointestinal Neuroendocrine Tumors Show Common MicroRNA Expression Profiles, Different from Adenocarcinomas and Small Cell Carcinomas.

BACKGROUND: It is still uncertain whether small cell lung carcinomas (SCLCs), pulmonary carcinoids, and the gastrointestinal neuroendocrine tumors (GI-NETs) have a common origin. MicroRNA (miRNA) expression may clarify their genetic relationships and origin. METHODS: First, we compared the miRNA expression signature of formalin-fixed paraffin-embedded (FFPE) samples with frozen samples to verify the applicability of microarray analysis. Second, we compared the comprehensive miRNA expression patterns of pulmonary carcinoids and GI-NETs as well as other types of tumors and normal tissues from each organ using FFPE samples. These data were analyzed by hierarchical clustering and consensus clustering with nonnegative matrix factorization. RESULTS: We confirmed that FFPE samples retained the miRNA signatures. In the first hierarchical clustering comparing carcinoids/NETs with adenocarcinomas and normal tissues, most of the carcinoids (48/50) formed 1 major cluster with loose subpartitioning into each organ type, while all the adenocarcinomas (9/9) and normal tissues (15/15) formed another major cluster. The nonnegative matrix factorization approach largely matched the classification of the hierarchical clustering. In the additional cluster analysis comparing carcinoids/NETs with SCLCs, most carcinoids/NETs (17/22) formed a major cluster, while SCLCs (9/9) grouped together with pulmonary adenocarcinomas (3/3) and normal tissues (6/6) in another major cluster. Furthermore, a subset of miRNAs was successfully identified that exhibited significant expression in carcinoids/NETs. CONCLUSION: Carcinoids/NETs had a characteristic pattern of miRNA expression, suggesting a common origin for pulmonary carcinoids and GI-NETs. The expression profiles of pulmonary carcinoids and SCLCs were quite different, indicating the distinct histogenesis of these neuroendocrine neoplasms.

Small Bowel and Colorectal Carcinoids.

Neuroendocrine tumors, or carcinoid tumors, of both the midgut and hindgut are quite rare, but their incidence is increasing. Surgery is the treatment of choice in patients who can tolerate an operation and have operable disease. Options for the treatment of metastatic disease include cytoreductive surgery, somatostatin analogues, interferon α, local liver therapies (hepatic arterial embolization, ablation), chemotherapy, Peptide-Receptor Radionucleotide Radiotherapy, angiogenesis inhibitors, and mammalian target of rapamycin inhibitors.

Radionuclide Therapy for Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) is a form of systemic radiotherapy that allows targeted delivery of radionuclides to tumor cells expressing high levels of somatostatin receptors. The two radiopeptides most commonly used for PRRT, 90Y-DOTATOC and 177Lu-DOTATATE, have been successfully employed for more than a decade for the treatment of advanced neuroendocrine tumors (NETs). Recently, the phase III, randomized NETTER-1 trial has compared 177Lu-DOTATATE versus high-dose octreotide LAR in patients with progressive, metastatic midgut NETs, demonstrating exceptional tolerability and efficacy. This review summarizes recent developments in the field of radionuclide therapy for gastroenteropancreatic and lung NETs and considers possible strategies to further enhance its clinical efficacy.

Development of a gastric carcinoid tumor following allogeneic hematopoietic stem cell transplantation for early T-cell precursor acute lymphoblastic leukemia.

Gastric carcinoid tumor is rarely diagnosed in children. We report a case of gastric carcinoid tumor that occurred after allogeneic HSCT. A 13-year-old girl with ETP acute lymphoblastic leukemia underwent allogeneic HSCT from a 7/8 HLA-matched unrelated donor. She presented with rashes, abdominal pain, and diarrhea, which were suggestive of GVHD, 7 months after HSCT. Immunosuppressive agents failed to resolve these symptoms well. After a series of evaluations, carcinoid syndrome caused by a gastric carcinoid tumor was diagnosed. The tumor was located in the antral region and resulted in partial gastric outlet obstruction. She received subtotal gastrectomy with regional lymph node dissection. However, she had a flare-up of GVHD 1 month after surgery, and immunosuppressive therapy was intensified accordingly. Although her GVHD was getting better, she developed respiratory syncytial viral pneumonia with rapid progression to respiratory failure. She died of multiple organ failure 2 months postoperatively. This is the first pediatric case of a gastric carcinoid tumor following allogeneic HSCT. Our case also highlights the necessity for pediatric transplant physicians to be aware of carcinoid syndrome caused by this rare tumor in the setting of GVHD with poor response to immunosuppressive agents.

Treatment Strategies for Metastatic Neuroendocrine Tumors of the Gastrointestinal Tract.

OPINION STATEMENT: The therapeutic landscape of gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) has evolved significantly in recent years. Current and emerging treatment options include somatostatin analogs, radiolabeled somatostatin analogs, the mTOR inhibitor everolimus, and the tyrosine kinase inhibitor sunitinib. Although high-quality data from phase III trials are lacking, cytotoxic agents are commonly used for the treatment of poorly differentiated neuroendocrine carcinomas and well-differentiated NETs originating in the pancreas. Hepatic-directed therapies are recommended for patients with slow-growing, liver-predominant disease but have never been compared to systemic agents. Telotristat ethyl, a novel serotonin synthesis inhibitor, has recently demonstrated efficacy in palliating diarrhea in patients with poorly controlled carcinoid syndrome. In the absence of definite predictive biomarkers, therapeutic decisions in most cases rely on clinical and pathological criteria. However, navigating the current therapeutic algorithm may be challenging, and future trials need to address several important questions: what is the best sequence of treatment? Is there a role for combination therapies in GEP-NETs? Are neoadjuvant, adjuvant, or maintenance strategies safe and effective? Do all NET patients require active treatment? What new molecular targets can be clinically exploited? A tight integration between basic and clinical research is needed to further advance the field of NETs.

Neuroendocrine Carcinoma of the Breast: Current Evidence and Future Perspectives.

UNLABELLED: : Neuroendocrine carcinoma of the breast is considered a rare entity, and for this reason there are no data from prospective clinical trials on its optimal management. Early stage tumors are usually treated with the same strategy used for the other types of invasive breast cancer. Anthracycline- and taxane-based regimens represent the most frequently administered chemotherapy in neoadjuvant and adjuvant setting, as well as for metastatic disease, although combinations of platinum compounds and etoposide have been widely used, in particular for small-cell histology and tumors with a high proliferation index. For metastatic disease, a multimodality therapeutic strategy can be considered on an individual basis, with chemotherapy, endocrine therapy, peptide receptor radionuclide therapy, radiation therapy, surgery, or a combination of the above. In the near future, a better knowledge of the biology of these tumors will hopefully provide new therapeutic targets for personalized treatment. In this review, we discuss the current evidence and the future perspectives on diagnosis and treatment of neuroendocrine carcinoma of the breast. IMPLICATIONS FOR PRACTICE: Neuroendocrine carcinoma of the breast (NECB) is a distinct entity of breast cancer. Clinical features and morphology are not helpful to distinguish NECB from other subtypes of breast cancer; therefore, immunohistochemistry markers for neuroendocrine differentiation, mainly chromogranin and synaptophysin, should be routinely used to confirm the diagnosis, especially in cases of mucinous or solid papillary carcinoma in which the suspicion of NECB may be relevant. Adjuvant treatment should be offered according to the same recommendations given for the other types of invasive breast cancer. An accurate diagnosis of NECB is also important in the metastatic setting, in which a multimodality approach including specific therapies such as peptide receptor radionuclide therapy can be considered.

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors.

UNLABELLED: : The carcinoid syndrome represents a set of signs and symptoms associated with neuroendocrine tumors (NETs) that occur primarily when metastases are developed in the liver, resulting in the worsening of quality of life. Serotonin plays a central role in the physiology of carcinoid syndrome by promoting intestinal motility. Somatostatin analogs (SSAs) have widely demonstrated their efficacy as symptomatic relievers of carcinoid syndrome, but this control is ephemeral, being reduced by approximately 50% within the first year. The exact mechanisms of resistance to SSAs are not fully understood, but it is believed that serotonin might be involved. Patients with carcinoid syndrome present with a significant increase in serotonin plasma levels and, consequently, in the soluble urinary metabolite 5-hydroxyindole acetic acid. Telotristat etiprate is a potent inhibitor of tryptophan hydroxylase, a rate-limiting enzyme in the synthesis of serotonin, that has demonstrated in the phase III TELESTAR clinical trial a significant improvement in the control of bowel movements in patients with NETs who have carcinoid syndrome and who have progressed to an SSA. Based on these results, telotristat etiprate has emerged as a potential new option in the treatment algorithm of symptomatic control of functioning NETs. However, some issues need to be clarified, such as the safety profile of the drug outside clinical trials, the benefit in quality of life, and the possible impact on tumor growth, as well as its role within sequencing or combination treatment strategies with pre-existing drugs effective in NET treatment. IMPLICATIONS FOR PRACTICE: This article reviews the literature about carcinoid syndrome, which affects patients diagnosed with neuroendocrine tumors. Few articles have been published about this syndrome and its pathophysiology. Somatostatin analogs provide symptomatic relief; however, patients may become refractory to this strategy, usually within the first year of treatment. In this context, as an agent with an innovative mechanism of action, telotristat etiprate has demonstrated activity in a phase III trial, and findings may offer a path to an improve quality of life and prolonged survival for certain patients.

New horizons for targeted treatment of neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare and heterogeneous tumors and there is a paucity of randomized clinical trials evaluating the different therapeutic strategies. Over recent years, some important molecular aspects have been investigated and multiple targeted therapies are currently available. One of the most promising targets for the therapy of NETs are the mTOR and angiogenic growth factor receptors. The advent of the inhibitors of the mTOR pathway, tyrosine kinase inhibitors and of somatostatin analogs have shown their efficacy in randomized clinical trials in terms of implementing clinical hormone-induced syndromes and progression-free survival of advanced NETs. This article summarizes the standard therapies and new perspectives in NET's treatment, which remains still very heterogeneous and little known entity.

Ten-year Single Center Experience of Pulmonary Carcinoid Tumors and Diagnostic Yield of Bronchoscopic Biopsy.

PURPOSE: Bronchoscopic biopsy of pulmonary carcinoid tumors has been controversial, and no study to date is dedicated to investigate diagnostic yield or safety. We reviewed our single center experience with pulmonary carcinoid tumors over a 10-year time period and assessed the diagnostic yield and safety of bronchoscopic biopsy of these tumors. METHODS: A retrospective analysis was conducted of all bronchopulmonary carcinoid tumors from January 2003 through January 2014 for patients treated at or referred to our tertiary care facility, including patient and tumor characteristics, diagnostic yield, and complications of bronchoscopy. RESULTS: Forty-nine patients with bronchopulmonary carcinoid tumors were identified. 75.5 % of our patients were female, and the median age was 60.7 years. 85.7 % patients were white, and 53.1 % were smokers. 83.7 % had typical carcinoid tumors or tumorlets, and 85.7 % had centrally located tumors. The median tumor size was 2.0 cm. Thirty patients underwent bronchoscopy for diagnostic evaluation. 76.7 % were diagnosed via bronchoscopic biopsy. Bronchoscopic yield was calculated at 65.7 % yield, and two complications of moderate to severe bleeding occurred with no emergent thoracotomies, transfusions, or deaths. No other complications occurred from bronchoscopy. CONCLUSION: The diagnosis of pulmonary carcinoid tumors via bronchoscopic biopsy is safe and effective, and bronchoscopy is recommended as the initial diagnostic modality for these tumors.